chr7-117559629-G-A

Position:

chr7-117559629-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM2PM5BP4_Strong

The NM_000492.4(CFTR):c.1558G>A(p.Val520Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000114 in 1,613,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V520F) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:16B:1

Conservation

PhyloP100: 4.96

Variant links:

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR links:

CFTR-AS1 (HGNC:):

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117559629-G-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.051140845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1558G>A	p.Val520Ile	missense_variant	11/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730
CFTR-AS1	NR_149084.1 linkuse as main transcript	n.221+1104C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1558G>A	p.Val520Ile	missense_variant	11/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000237

AC:

AN:

152038

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000147

AC:

AN:

251102

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000979

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

148

AN:

1460978

Hom.:

Cov.:

AF XY:

0.0000784

AC XY:

AN XY:

726852

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000909

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.000237

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.000506

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00155

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000267

Hom.:

Bravo

AF:

0.000264

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:16Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:5Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 28, 2022	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 520 of the CFTR protein (p.Val520Ile). This variant is present in population databases (rs77646904, gnomAD 0.08%). This missense change has been observed in individuals with congenital absence of vas deferens and/or cystic fibrosis (PMID: 12167682, 14998948, 16596947, 17020473, 19324992, 30811104). ClinVar contains an entry for this variant (Variation ID: 35825). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Val520 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23891399, 23974870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 03, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	CFTR: PM5, BP2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 02, 2024	The CFTR c.1558G>A (p.Val520Ile) variant has been reported in the published literature in individuals with cystic fibrosis and/or congenital absence of the vas deferens (PMIDs: 32777524 (2021), 30811104 (2019), 19324992 (2009), 14998948 (2004), and 12167682 (2002)), as well as bronchiectasis (PMID: 29997923 (2018)). The frequency of this variant in the general population, 0.001 (20/19950 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 06, 2019	The CFTR c.1558G>A; p.Val520Ile variant (rs77646904) has been reported in the literature in individuals with mild or atypical cystic fibrosis, including in individuals with congenital bilateral absence of the vas deferens (Bienvenue 2005, Danziger 2004, Groman 2002, Guan 2018, Schwartz 2009, Yuan 2019), but in many cases a second CFTR variant was not identified. Additionally, another variant in the same codon, p.Val520Phe, is a known pathogenic variant (Sosnay 2013). The p.Val520Ile variant is reported in ClinVar (Variation ID: 35825) and is found in general population with an overall allele frequency of 0.015% (43/282480 alleles) in the Genome Aggregation Database. The valine at codon 520 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.486). Due to limited information, the clinical significance of the p.Val520Ile variant is uncertain at this time. References: Bienvenu T et al. Spectrum of CFTR mutations on Reunion Island: impact on neonatal screening. Hum Biol. 2005. 77(5):705-14. Danziger KL et al. Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis. Hum Reprod. 2004. 19(3):540-6. Groman JD et al. Variant cystic fibrosis phenotypes in the absence of CFTR mutations. N Engl J Med. 2002. 347(6):401-7. Guan WJ et al. Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. J Thorac Dis. 2018 May;10(5):2618-2630. Schwartz K et al. Identification of cystic fibrosis variants by polymerase chain reaction/oligonucleotide ligation assay. J Mol Diagn. 2009. 11(3):211-5. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013. 45(10):1160-7. Yuan P et al. Expanding the phenotypic and genetic spectrum of Chinese patients with congenital absence of vas deferens bearing CFTR and ADGRG2 alleles. Andrology. 2019 May;7(3):329-340. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 27, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 05, 2020	- -

CFTR-related disorder

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 09, 2024	The CFTR c.1558G>A variant is predicted to result in the amino acid substitution p.Val520Ile. This variant has been reported in individuals affected with CFTR-related disorders including cystic fibrosis (Bienvenu et al. 2005. PubMed ID: 16596947), non-classic cystic fibrosis (Groman et al. 2002. PubMed ID: 12167682), congenital bilateral absence of the vas deferens (Danziger et al. 2004. PubMed ID: 14998948; Yuan et al. 2019. PubMed ID: 30811104), and bronchitis (Nectoux et al. 2006. PubMed ID: 17020473). However, a second pathogenic CFTR variant was not identified or specified in these patients. This variant was also identified in the heterozygous state in an individual of unknown phenotype undergoing either diagnostic or carrier testing in the CFTR gene (Schwartz et al. 2009. PubMed ID: 19324992). An alternative nucleotide substitution resulting in a different missense change at the same amino acid position (p.Val520Phe) has been reported as causative for cystic fibrosis (Sosnay et al. 2013. PubMed ID: 23974870, Van Goor et al. 2014. PubMed ID: 23891399). However, at this time, the clinical significance of the c.1558G>A (p.Val520Ile) variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary pancreatitis

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jun 19, 2023	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	May 18, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 30, 2024

Variant summary: CFTR c.1558G>A (p.Val520Ile) results in a conservative amino acid change located in the AAA+ ATPase domain and ABC transporter-like domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251302 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00015 vs 0.013), allowing no conclusion about variant significance. c.1558G>A has been reported in the literature in individuals affected with Cystic Fibrosis or CFTR-related disorders (e.g. CBAVD, bronchiectasis) (e.g. Bienvenu_2005, Danziger_2004, Guan_2018, Nectoux_2006, Yuan_2019, Luo_2021) and also other phenotypes such as lung adenocarcinoma, non-obstructive azoospermia or severe oligozoospermia and pancreatic cancer (e.g. Donner_2018, Oud_2017, Tamura_2018, Smits_2019). In further detail, the variant was seen in a CF patient with a mild disease who had no other CFTR mutations (Nectoux_2006) and in an Indian CF patient who had an unknown mutation on his other CF chromosome (Sick Kids database). In addition, the variant was observed in a CF patient who also carried 2347delG and deltaF508 mutations (Bienvenu_2005). These co-occurrences indicate that the variant may be in the benign spectrum. Furthermore, c.1558G>A has been documented in CBAVD patients who were reported to also carry 3601-3C>A (c.3469-3C>A as per HGVS nomenclature) (Danziger_2004) and c.2042A>T (Yuan_2019). Claustres et al (2017) report the variant in trans with p.K710X being observed in an asymptomatic compound heterozygote individual. Taken together, these reports do not allow for unequivocal conclusions about association of the variant with cystic fibrosis. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1558G>T, p.Val520Phe), supporting the critical relevance of codon 520 to CFTR protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately ~41% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 12167682, 17020473, 16596947, 14998948, 24517344, 25087612, 25735457, 18937943, 26708955, 28603918, 28801929, 29997923, 29669919, 30032850, 30811104, 31672438, 32777524, 34996830, 38388235). ClinVar contains an entry for this variant (Variation ID: 35825). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Uncertain

0.052

BayesDel_noAF

Pathogenic

0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.;.;D;.

Eigen

Benign

0.065

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.051

T;T;T;T;T

MetaSVM

Uncertain

0.047

MutationAssessor

Benign

1.4

L;.;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.89

N;.;.;N;.

REVEL

Uncertain

0.58

Sift

Benign

0.047

D;.;.;D;.

Sift4G

Benign

0.064

T;.;.;T;.

Polyphen

0.063

B;.;.;.;.

Vest4

0.74

MVP

0.97

MPC

0.011

ClinPred

0.022

GERP RS

5.5

Varity_R

0.58

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over